Synthesis and Ring-Closing Reactions of Aminocyclohexane Derivatives Bearing Unsaturated Side Chains at C2: Stereocontrolled Approaches to cis- and trans-Fused Perhydro-indoles and -Quinolines

Two epimeric pairs of N-Ts-protected cyclohexylamines that incorporate an unsaturated side-chain at the C2 position have been prepared. Contrary to expectations, none of these underwent clean, photochemically-induced intramolecular hydroamination reactions to give the corresponding perhydro-indole or -quinoline. However, they did participate in efficient olefin cross metathesis (OCM) reactions with methyl crotonate. Three of the four acrylates so-formed engaged in base-promoted and completely diastereoselective, intramolecular aza-Michael addition (cyclization) reactions to give the isomeric and C2-substituted perhydro-indoles or -quinolines with the structures of these being confirmed by single-crystal X-ray analyses. DFT calculations generated results consistent with the observed diastereoselectivities and the proposed transition states. Manipulation of the ester groups associated with the cyclization products allowed for their conversion, inter alia, into the corresponding n-propyl residues and thus providing novel analogues of neurotoxic alkaloids such as pumiliotoxin C.